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    Anticonvulsants, Miscellaneous

    DEA CLASS

    Rx

    DESCRIPTION

    Triazole derivative anticonvulsant
    Used for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome
    Approved for use in patients >= 1 year

    COMMON BRAND NAMES

    Banzel

    HOW SUPPLIED

    Banzel Oral Susp: 1mL, 40mg
    Banzel Oral Tab: 200mg, 400mg

    DOSAGE & INDICATIONS

    For the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.
    Oral dosage
    Adults and Adolescents >= 17 years

    Initially, 400—800 mg/day PO in 2 equally divided doses. Patients on valproate should begin rufinamide at a dose lower than 400 mg/day. The dosage should be increased every other day by 400—800 mg/day to a target and maximum dose of 3200 mg/day given in 2 equally divided doses. It is not known whether doses less than 3200 mg/day are effective. If drug discontinuation is necessary, rufinamide should be withdrawn gradually (e.g., 25% dose reduction every 2 days) to minimize the potential for increased seizure frequency.

    Children and Adolescents 1—16 years

    Initially, 10 mg/kg/day PO given as 2 equally divided doses. Pediatric patients receiving valproate should begin rufinamide at a dose lower than 10 mg/kg/day. The dose should be increased every other day by 10 mg/kg to a target dose of 45 mg/kg/day or 3200 mg/day, whichever is less, given in 2 equally divided doses. If drug discontinuation is necessary, rufinamide should be withdrawn gradually (e.g., 25% dose reduction every 2 days) to minimize the potential for increased seizure frequency.

    For the adjunctive treatment of refractory partial seizures†.
    Oral dosage
    Adults

    3200 mg/day PO given in 2 divided doses was compared to placebo in a study of approximately 3 months duration (n=313). Subjects in the rufinamide group had a 20.4% decrease in median seizure frequency compared to baseline versus a 1.6% median increase in the placebo group. In a separate study (n=647), subjects were randomized to placebo or rufinamide (200 mg, 400 mg, 800 mg, or 1600 mg/day given in 2 divided doses). Subjects receiving rufinamide experienced a statistically significant reduction in the primary efficacy variable, seizure frequency per 28 days, compared to those receiving placebo. NOTE: For the treatment of seizures associated with Lennox-Gastaut syndrome, the manufacturer recommends dosage titration over several days to the target dose.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    3200 mg/day PO.

    Geriatric

    3200 mg/day PO.

    Adolescents

    17 years: 3200 mg/day PO.
    13—16 years: 45 mg/kg/day PO (Max: 3200 mg/day).

    Children

    45 mg/kg/day PO (Max: 3200 mg/day).

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use in patients with severe hepatic impairment (Child-Pugh score 10—15) is not recommended. Exercise caution in patients with mild (Child-Pugh score 5—6) to moderate (Child-Pugh score 7—9) impairment. Rufinamide has not been studied in patients with hepatic impairment.

    Renal Impairment

    No dosage adjustments are needed.
     
    Intermittent hemodialysis
    Hemodialysis reduces exposure of rufinamide by approximately 30%. This reduction should be considered when dosing rufinamide in patients receiving dialysis.

    ADMINISTRATION

     
    A MedGuide that provides information about the proper use and risks of rufinamide should be dispensed with each new prescription and refill. The MedGuide also discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications.

    Oral Administration

    Administer all dosage forms orally with food.

    Oral Solid Formulations

    Tablets may be administered whole, crushed, or halved. Give with food.

    Oral Liquid Formulations

    Oral Suspension:
    Shake well before every use.
    Administer with the provided adapter and calibrated oral dosing syringe. Insert adapter firmly into the neck of the bottle before use and keep in place for the duration of the bottle usage.
    The dosing syringe should be inserted into the adapter and the dose withdrawn from the inverted bottle.
    Replace cap after each use. The cap fits properly when the adapter is in place.
    Use within 90 days of first opening the bottle, then discard any remaining amount.
    Give with food.

    STORAGE

    Banzel:
    - Discard opened bottle after 90 days
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Rufinamide is contraindicated in patients who have demonstrated rufinamide-hypersensitivity. A case of multi-organ hypersensitivity syndrome (e.g., rash, urticaria, facial edema, fever, eosinophilia, stupor, and hepatitis) was observed in one patient during clinical trials. Other possible cases were observed in pediatric patients less than 12 years of age within 4 weeks of treatment initiation. If a multi-organ hypersensitivity reaction is suspected, rufinamide should be discontinued. Patients should be instructed to promptly report potential signs of multi-organ hypersensitivity reactions, such as fever or rash, to their health care provider. All patients who develop a rash during treatment with rufinamide should be closely monitored.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants like rufinamide to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2—2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this risk is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Short QT syndrome, shortened QT interval

    Rufinamide is contraindicated for use in patients with familial short QT syndrome. A higher percentage of subjects who took rufinamide during placebo-controlled clinical trials had a QT interval shortening of more than 20 milliseconds compared to placebo. Reductions in the QT interval below 300 milliseconds were not observed with rufinamide doses up to 7,200 mg/day. Familial short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation, which are believed to occur primarily when the corrected QT interval falls below 300 milliseconds. Nonclinical data also indicate that QT shortening is associated with ventricular fibrillation. Use caution when administering runfinamide with other drugs that cause a shortened QT interval as there may be a synergistic effect on the QT interval that would increase the QT shortening risk.[34590]

    Abrupt discontinuation

    Abrupt discontinuation of rufinamide therapy should not be undertaken. If discontinuation becomes necessary, rufinamide should be withdrawn gradually (e.g., 25% every two days) to minimize the potential for seizure exacerbation or status epilepticus.

    Driving or operating machinery

    Rufinamide may cause drowsiness, dizziness, coordination abnormalities, gait disturbances, and ataxia. Patients should be advised to avoid driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether rufinamide adversely affects their cognitive and/or motor performance. Patients should also be informed of the possibility for enhanced drowsiness or dizziness with concurrent use of alcohol.

    Dialysis

    Limited data indicate that the pharmacokinetics of rufinamide are not affected by the presence of severe renal impairment (CrCl < 30 ml/min). However, hemodialysis reduces exposure of rufinamide by approximately 30%. This reduction should be considered when dosing rufinamide in patients receiving dialysis.

    Hepatic disease

    Rufinamide is not recommended in patients with severe hepatic impairment because the drug has not been studied in this patient population. Careful dose titration is advisable in patients with mild to moderate hepatic disease since rufinamide is extensively metabolized via the liver.

    Geriatric

    The number of geriatric patients enrolled in clinical trials of rufinamide was insufficient to determine if differences in response existed compared to younger adults. Because geriatric patients are more likely to have decreased renal, hepatic, or cardiac function, careful dose titration is advised. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If rufinamide must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.[60742]

    Pregnancy

    There are no adequate data on the developmental risks associated with rufinamide use during human pregnancy. In animal reproduction studies, oral administration of rufinamide resulted in developmental toxicity in pregnant rats and rabbits at clinically relevant doses. Decreased fetal weight and increased incidence of fetal skeletal abnormalities occurred with oral administration of rufinamide (0, 20, 100, or 300 mg/kg/day) to pregnant rats throughout organogenesis. The maternal plasma exposure (AUC) at the no adverse effect dose (20 mg/kg/day) for developmental toxicity was less than that in humans at the maximum recommended human dose (MRHD) of 3,200 mg/day. Embryofetal death, decreased fetal body weight, and increased incidence of fetal visceral and skeletal abnormalities occurred with oral administration of rufinamide (0, 30, 200 and 1,000 mg/kg/day) to pregnant rabbits throughout organogenesis at doses of 200 and 1,000 mg/kg/day. The high dose (1,000 mg/kg/day) was associated with abortion. Plasma exposure (AUC) at the no-adverse effect dose (30 mg/kg/day) was less than that in humans at the MRHD. Decreased offspring growth and survival were observed at all rufinamide doses (0, 5, 30, or 150 mg/kg/day) given to rats throughout pregnancy and lactation. At the lowest dose (5 mg/kg/day), plasma exposure (AUC) was less than that in humans at the MRHD. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to rufinamide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[34590]

    Breast-feeding

    There are no data on the presence of rufinamide in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for rufinamide and any potential adverse effects on the breast-fed infant from rufinamide or the underlying maternal condition.[34590]

    Infertility, reproductive risk

    Rufinamide may be associated with reproductive risk. The effect of rufinamide on fertility in humans has not been established. Oral administration of rufinamide (20, 60, 200, and 600 mg/kg/day) to male and female rats prior to mating, during mating, and during early gestation (females only) resulted in infertility at all doses. The no-effect dose was not established. The plasma exposure level at 20 mg/kg was approximately 0.2 times the human plasma AUC at the MRHD.[34590]

    ADVERSE REACTIONS

    Severe

    AV block / Early / 0.1-1.0
    suicidal ideation / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

    Moderate

    shortened QT interval / Delayed / 46.0-65.0
    constipation / Delayed / 3.0-12.0
    nystagmus / Delayed / 6.0-6.0
    blurred vision / Early / 6.0-6.0
    ataxia / Delayed / 4.0-5.4
    nephrolithiasis / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    dysuria / Early / 0.1-1.0
    bundle-branch block / Early / 0.1-1.0
    hematuria / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    infertility / Delayed / Incidence not known

    Mild

    headache / Early / 16.0-27.0
    drowsiness / Early / 11.0-24.0
    vomiting / Early / 5.0-24.0
    dizziness / Early / 2.7-19.0
    fatigue / Early / 9.0-16.0
    nausea / Early / 7.0-12.0
    cough / Delayed / 12.0-12.0
    diplopia / Early / 4.0-9.0
    weight loss / Delayed / 8.0-8.0
    infection / Delayed / 3.0-8.0
    nasal congestion / Early / 8.0-8.0
    tremor / Early / 6.0-6.0
    influenza / Delayed / 5.0-5.0
    pharyngitis / Delayed / 5.0-5.0
    vertigo / Early / 3.0-3.0
    anxiety / Delayed / 3.0-3.0
    dyspepsia / Early / 3.0-3.0
    abdominal pain / Early / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    sinusitis / Delayed / 3.0-3.0
    polyuria / Early / 0.1-1.0
    nocturia / Early / 0.1-1.0
    appetite stimulation / Delayed / 1.0
    anorexia / Delayed / 1.0
    rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    Amiodarone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as amiodarone, may occur during concurrent use with rufinamide.
    Amphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Amphetamine; Dextroamphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Amphetamines: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Rufinamide is metabolized by carboxylesterases. The clearance of rufinamide may be increased due to induction of carboxylesterases by phenobarbital. (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with rufinamide may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with rufinamide to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking rufinamide, reduce initial dosage and titrate to clinical response. If rufinamide is initiated a patient taking an opioid agonist, use a lower initial dose of rufinamide and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Bepridil: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as bepridil, may occur during concurrent use with rufinamide.
    Bortezomib: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as bortezomib, may occur during concurrent use with rufinamide.
    Buprenorphine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as buprenorphine, may occur during concurrent use with rufinamide.
    Buprenorphine; Naloxone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as buprenorphine, may occur during concurrent use with rufinamide.
    Busulfan: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as busulfan, may occur during concurrent use with rufinamide.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and rufinamide. CNS depressants can potentiate the effects of cannabidiol.
    Carbamazepine: (Moderate) Rufinamide is metabolized by carboxylesterases. The clearance of rufinamide may be increased due to induction of carboxylesterases by carbamazepine.
    Cenobamate: (Moderate) Use caution when administering cenobamate and rufinamide due to the potential for a synergistic effect on the QT interval that would increase the QT shortening risk. Both cenobamate and rufinamide are associated with QT shortening. Nonclinical data indicate that QT shortening is associated with ventricular fibrillation.
    Chlorzoxazone: (Moderate) In theory, plasma concentrations of chlorzoxazone or other CYP2E1 substrates may be increased due to the weak 2E1 inhibitory effects of rufinamide.
    Cilostazol: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cilostazol, may occur during concurrent use with rufinamide.
    Cisapride: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cisapride, may occur during concurrent use with rufinamide.
    Cyclosporine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cyclosporine, may occur during concurrent use with rufinamide.
    Dapsone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as dapsone, may occur during concurrent use with rufinamide.
    Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as rufinamide, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dextroamphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Dextromethorphan; Quinidine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as quinidine, may occur during concurrent use with rufinamide.
    Dihydroergotamine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Docetaxel: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as docetaxel, may occur during concurrent use with rufinamide.
    Donepezil: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as donepezil, may occur during concurrent use with rufinamide.
    Donepezil; Memantine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as donepezil, may occur during concurrent use with rufinamide.
    Ergoloid Mesylates: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Ergonovine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Ergot alkaloids: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Ergotamine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Ergotamine; Caffeine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Ethanol: (Moderate) The use of alcohol in combination with rufinamide may cause additive central nervous system depressant effects. (Moderate) The use of ethanol in combination with rufinamide may cause additive central nervous system depressant effects.
    Ethosuximide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as ethosuximide, may occur during concurrent use with rufinamide.
    Fosphenytoin: (Moderate) A population pharmacokinetic analysis showed an increase of 7 to 21% in phenytoin concentrations and a decrease of 25 to 46% in rufinamide concentrations during concurrent use. A similar interaction may be expected to occur with fosphenytoin.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as rufinamide. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Isavuconazonium: (Moderate) Use caution when administering rufinamide and isavuconazonium due to the potential for a synergistic effect on the QT interval that would increase the QT shortening risk. Both rufinamide and isavuconazonium are associated with QT shortening. Nonclinical data indicate that QT shortening is associated with ventricular fibrillation.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., rufinamide), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lamotrigine: (Moderate) Shortening of the QT interval has occurred during treatment with rufinamide. Therefore, caution is advisable during co-administration with other drugs associated with QT-shortening including lamotrigine. In addition, a population pharmacokinetic analysis showed a 7% to 13% decrease in lamotrigine concentrations and no effect on rufinamide concentrations during concurrent use.
    Levobupivacaine: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as levobupivacaine, may occur during concurrent use with rufinamide.
    Lisdexamfetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Macimorelin: (Major) Discontinue rufinamide and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer.
    Methamphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Methylergonovine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Methysergide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Midazolam: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as midazolam, may occur during concurrent use with rufinamide.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Nanoparticle Albumin-Bound Sirolimus: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as sirolimus, may occur during concurrent use with rufinamide.
    Nefazodone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as nefazodone, may occur during concurrent use with rufinamide.
    Non-oral combination contraceptives: (Major) Coadministration of hormonal contraceptives with rufinamide may reduce hormone concentrations and therefore reduce the clinical efficacy of hormonal contraceptives. If coadministration is necessary, recommend patients use additional non-hormonal forms of contraception. Hormonal contraceptives are metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer.
    Oral Contraceptives: (Major) Coadministration of hormonal contraceptives with rufinamide may reduce hormone concentrations and therefore reduce the clinical efficacy of hormonal contraceptives. If coadministration is necessary, recommend patients use additional non-hormonal forms of contraception. Hormonal contraceptives are metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer.
    Paclitaxel: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as paclitaxel, may occur during concurrent use with rufinamide.
    Paricalcitol: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as paricalcitol, may occur during concurrent use with rufinamide.
    Pergolide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Phenobarbital: (Moderate) Rufinamide is metabolized by carboxylesterases. The clearance of rufinamide may be increased due to induction of carboxylesterases by phenobarbital.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Rufinamide is metabolized by carboxylesterases. The clearance of rufinamide may be increased due to induction of carboxylesterases by phenobarbital.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant rufinamide, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Phenytoin: (Moderate) A population pharmacokinetic analysis showed an increase of 7 to 21% in phenytoin concentrations and a decrease of 25 to 46% in rufinamide concentrations during concurrent use. A similar interaction may be expected to occur with fosphenytoin.
    Primidone: (Moderate) A population pharmacokinetic analysis showed a decrease in rufinamide concentrations during concurrent use of primidone.
    Quinidine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as quinidine, may occur during concurrent use with rufinamide.
    Quinine: (Minor) The potential interaction between quinine and rufinamide is unpredictable. CYP isozymes 3A4 and, to a lesser extent, 2E1 are involved in quinine metabolism. In theory, plasma concentrations of CYP2E1 substrates may be increased due to the weak 2E1 inhibitory effects of rufinamide. Conversely, the weak CYP3A4 inducer effects of rufinamide may result in decreased exposure of drugs that are metabolized by this isozyme.
    Sibutramine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as sibutramine, may occur during concurrent use with rufinamide.
    Sirolimus: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as sirolimus, may occur during concurrent use with rufinamide.
    Tacrolimus: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as tacrolimus, may occur during concurrent use with rufinamide.
    Telithromycin: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as telithromycin, may occur during concurrent use with rufinamide.
    Terfenadine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as terfenadine, may occur during concurrent use with rufinamide.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant rufinamide, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Trimetrexate: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as trimetrexate, may occur during concurrent use with rufinamide.
    Valproic Acid, Divalproex Sodium: (Major) A population pharmacokinetic analysis showed no effect on valproate concentrations and an increase of less than 16 to 70% in rufinamide concentrations during concurrent use. Adult patients currently stabilized on valproic acid or divalproex should initiate rufinamide therapy at a dosage lower than 400 mg/day, and pediatric patients stabilized on valproate therapy should begin rufinamide at a dose lower than 10 mg/kg/day. Similarly, patients stabilized on rufinamide before being prescribed valproate should initiate valproate therapy at a low dose followed by careful titration.
    Zolpidem: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as zolpidem, may occur during concurrent use with rufinamide.
    Zonisamide: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as zonisamide, may occur during concurrent use with rufinamide.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate data on the developmental risks associated with rufinamide use during human pregnancy. In animal reproduction studies, oral administration of rufinamide resulted in developmental toxicity in pregnant rats and rabbits at clinically relevant doses. Decreased fetal weight and increased incidence of fetal skeletal abnormalities occurred with oral administration of rufinamide (0, 20, 100, or 300 mg/kg/day) to pregnant rats throughout organogenesis. The maternal plasma exposure (AUC) at the no adverse effect dose (20 mg/kg/day) for developmental toxicity was less than that in humans at the maximum recommended human dose (MRHD) of 3,200 mg/day. Embryofetal death, decreased fetal body weight, and increased incidence of fetal visceral and skeletal abnormalities occurred with oral administration of rufinamide (0, 30, 200 and 1,000 mg/kg/day) to pregnant rabbits throughout organogenesis at doses of 200 and 1,000 mg/kg/day. The high dose (1,000 mg/kg/day) was associated with abortion. Plasma exposure (AUC) at the no-adverse effect dose (30 mg/kg/day) was less than that in humans at the MRHD. Decreased offspring growth and survival were observed at all rufinamide doses (0, 5, 30, or 150 mg/kg/day) given to rats throughout pregnancy and lactation. At the lowest dose (5 mg/kg/day), plasma exposure (AUC) was less than that in humans at the MRHD. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to rufinamide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[34590]

    There are no data on the presence of rufinamide in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for rufinamide and any potential adverse effects on the breast-fed infant from rufinamide or the underlying maternal condition.[34590]

    MECHANISM OF ACTION

    Mechanism of Action: The exact mechanism by which rufinamide exerts its anticonvulsant effects is unknown. In vitro data suggest that the drug exerts its therapeutic effects through modulation of sodium channels, primarily through prolongation of the inactive state of the channel. Rufinamide slows sodium channel recovery from inactivation and limits sustained repetitive firing of sodium-dependent action potentials.

    PHARMACOKINETICS

    Rufinamide is administered orally. The volume of distribution is 50 liters at a dose of 3200 mg/day. Protein-binding is not considered to be clinically relevant (34%). Rufinamide is extensively metabolized in the liver, primarily to an inactive carboxylic acid metabolite produced via enzymatic hydrolysis. Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4. The elimination half-life is 6—10 hours. Less than 2% of a dose is excreted unchanged in the urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2E1, CYP3A4
    Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4.

    Oral Route

    The oral suspension is bioequivalent on a mg per mg basis to the tablet formulation. Following an oral dose, rufinamide tablets are well absorbed (>= 85%) under fed conditions; however, the rate of absorption is slow and the extent of absorption decreases with increasing doses. Food increases the extent of tablet absorption by 34% and peak exposure by 56%. Because clinical trials were conducted under fed conditions, administration with food is recommended. Maximum plasma concentrations occur 4—6 hours after administration under fed and fasted conditions.